What are the clinical presentation, diagnostic workup, and treatment options for Myasthenia gravis, especially with ocular symptoms and how to differentiate it from thyroid eye disease?

Myasthenia Gravis: Clinical Presentation, Diagnosis, and Management

Clinical Presentation

Myasthenia gravis presents with fluctuating, fatigable muscle weakness that characteristically worsens with repetitive use and improves with rest, most commonly beginning with ocular symptoms before potentially progressing to life-threatening generalized disease. 1

Ocular Manifestations (Most Common Initial Presentation)

• Ptosis (drooping eyelids) appears unilateral or bilateral and characteristically worsens with sustained upgaze or prolonged activity, improving after rest periods 1, 2
• Diplopia (double vision) results from asymmetric, variable extraocular muscle weakness that changes during examination 1, 2
• Variable strabismus (eye misalignment) fluctuates throughout the day depending on fatigue level 3, 2
• Pupils are characteristically spared—this is a critical distinguishing feature that immediately differentiates myasthenia gravis from third nerve palsy 1, 2
• Approximately 50% of patients initially present with purely ocular symptoms 3, 2, 4

Bulbar and Facial Manifestations

• Dysarthria (slurred speech) worsens with prolonged talking 1, 2
• Dysphagia (difficulty swallowing) is a red-flag symptom requiring urgent assessment, as it is present in more than 50% of cases that precede myasthenic crisis 1, 2
• Facial muscle weakness causes reduced facial expressions 1, 3
• Hoarseness suggests bulbar involvement and warrants immediate evaluation 1, 2

Limb and Respiratory Involvement

• Proximal muscle weakness affects shoulders and hips more than distal muscles 1, 2
• Neck weakness with difficulty holding up the head may progress to respiratory involvement 1, 2
• Respiratory muscle weakness represents the most life-threatening manifestation and can rapidly progress to respiratory failure (myasthenic crisis) requiring intubation 1, 3

Key Clinical Characteristics

• Fluctuation: Symptoms vary in severity throughout the day and can present with completely different patterns depending on fatigue level or time of examination 2
• Fatigability: Weakness worsens with sustained or repeated muscle use and improves after rest periods 1, 2
• Variable presentation: The pattern of weakness changes during examination, making myasthenia gravis a "great masquerader" 3

Critical Prognostic Information

50-80% of patients presenting with isolated ocular symptoms will progress to generalized myasthenia gravis within a few years, most commonly within the first two years after onset. 1, 2

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Diagnostic Workup

Bedside Clinical Tests (Perform Immediately)

Ice Pack Test (Highly Specific)

• Apply an ice pack over closed eyelids for 2 minutes when assessing ptosis and for 5 minutes when assessing strabismus or ophthalmoplegia 1
• Before ice application, measure baseline ptosis using marginal reflex distance (MRD) and quantify ocular misalignment in prism diopters with cover testing 1
• A positive test is defined as improvement of ptosis by ≥2 mm or reduction in ocular deviation by ≥50% (or by ≥10 prism diopters when baseline deviation exceeds 20 PD) 1
• The physiologic basis is that cooling slows acetylcholine breakdown, allowing limited acetylcholine to remain longer in the synaptic cleft and partially offset reduced receptor availability 1

Rest Test

• Have the patient keep eyes closed for several minutes; improvement in ptosis and strabismus supports myasthenia gravis, though this is less standardized than the ice pack test 1

Edrophonium (Tensilon) Test

• Demonstrates 86% sensitivity for ocular myasthenia gravis but must be performed in a monitored setting with atropine (0.4-0.5 mg IV) readily available to treat potential muscarinic side effects (excessive tearing, salivation, sweating, bradycardia, bronchospasm, hypotension, syncope) 1

Serologic Testing

• Acetylcholine receptor (AChR) antibodies: Present in approximately 85% of generalized myasthenia gravis and 40-77% of ocular myasthenia gravis 1, 3, 4
• Anti-muscle-specific kinase (MuSK) antibodies: Should be ordered in seronegative cases, as approximately one-third of seronegative patients are MuSK-positive 1, 3
• Anti-lipoprotein-related protein 4 (LRP4) antibodies: Associated with both generalized and ocular myasthenia gravis and should be considered in seronegative cases 1, 3
• Antistriated muscle antibodies: Recommended by the American Academy of Neurology as part of comprehensive diagnostic testing 1

Electrodiagnostic Studies

• Single-fiber electromyography (SFEMG): Has sensitivity >90% for ocular myasthenia gravis and is regarded as the gold-standard test; a negative SFEMG result is atypical and warrants reconsideration of the differential diagnosis 1
• Repetitive nerve stimulation: Recommended by the American Academy of Neurology, though standard EMG and nerve conduction studies may be normal early in disease course 1

Imaging Studies

• Chest CT: Screen for thymoma, which is present in 10-15% of myasthenia gravis patients; 30-50% of thymoma patients have myasthenia gravis 1, 3
• Orbital CT/MRI: Differentiates thyroid eye disease (tendon-sparing muscle enlargement) from myasthenia gravis 1
• Brain imaging: May help exclude brainstem strokes that can mimic myasthenia gravis 1

Additional Workup

• Pulmonary function tests (negative inspiratory force [NIF] and vital capacity [VC]): Crucial for monitoring respiratory involvement, especially in patients with dysphagia or shortness of breath 1, 3
• CPK, aldolase, troponin T, ECG, echocardiography: Evaluate for concurrent myositis or myocarditis, particularly in patients with respiratory insufficiency or elevated CPK 1, 3
• Thyroid function tests and thyroid antibodies: Screen for autoimmune thyroid disease, which frequently coexists with myasthenia gravis 3, 5
• Cerebrospinal fluid examination: Typically normal in myasthenia gravis, which helps distinguish it from Guillain-Barré syndrome where CSF protein is often elevated by week 2 1

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Differentiating Myasthenia Gravis from Thyroid Eye Disease

Key Distinguishing Features

Feature	Myasthenia Gravis	Thyroid Eye Disease
Mechanism	Neuromuscular junction dysfunction [1]	Restrictive myopathy with mechanical limitation [1]
Weakness pattern	Fatigable, fluctuating weakness [1,2]	Fixed mechanical restriction [1]
Proptosis	Absent [1]	Present (hallmark feature) [1]
Eyelid retraction	Absent [1]	Present [1]
Ice pack test	Positive (improves ptosis/diplopia) [1]	Negative [1]
Forced duction testing	Normal (no mechanical restriction) [1]	Confirms mechanical restriction [1]
Orbital imaging	Normal muscle appearance [1]	Tendon-sparing muscle enlargement [1]
Diurnal variation	Worsens with fatigue, improves with rest [1,2]	Stable throughout day [1]
Pupillary involvement	Never affected [1,2]	Not typically affected [1]

Clinical Approach to Differentiation

• Assess for proptosis and eyelid retraction: Their presence strongly suggests thyroid eye disease rather than myasthenia gravis 1
• Perform ice pack test: Improvement of ptosis by ≥2 mm is highly specific for myasthenia gravis 1
• Perform forced duction testing: Mechanical restriction confirms thyroid eye disease versus fatigable weakness in myasthenia 1
• Order orbital imaging: Tendon-sparing muscle enlargement is characteristic of thyroid eye disease, while myasthenia gravis shows normal muscle appearance 1
• Observe temporal pattern: Fluctuating weakness that worsens with fatigue and improves with rest indicates myasthenia gravis, while stable symptoms throughout the day suggest thyroid eye disease 1, 2

Important Clinical Caveat

Myasthenia gravis and autoimmune thyroid disease (particularly Graves' disease) frequently coexist, with myasthenia gravis associated with autoimmune thyroid disease showing preferential ocular involvement and milder clinical expression. 5, 6 Therefore, both conditions may be present simultaneously, and treating one pathology may worsen the other 5. Always screen for thyroid disease in myasthenia gravis patients and vice versa 3, 5.

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Treatment Options

Classification-Based Treatment Algorithm

The Myasthenia Gravis Foundation of America (MGFA) classification guides treatment decisions 1, 2:

• Class I: Ocular symptoms only
• Class II: Mild generalized weakness
• Class III: Moderate generalized weakness
• Class IV: Severe generalized weakness
• Class V: Myasthenic crisis requiring intubation

First-Line Treatment (Class I-II)

• Pyridostigmine (acetylcholinesterase inhibitor): Start at 30 mg orally three times daily and gradually increase to maximum 120 mg orally four times daily as tolerated 1, 3
• Important limitation: Approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone, potentially requiring escalation to corticosteroids 1

Second-Line Treatment (Class II or Higher with Inadequate Response)

• Prednisone: 1-1.5 mg/kg orally daily, with approximately 66-85% of patients showing a positive response 1, 3
• Taper gradually based on symptom improvement 1

Third-Line Treatment (Moderate to Severe Disease)

• Azathioprine: Used as steroid-sparing immunosuppressive therapy 1, 3

Acute Treatment for Moderate to Severe Symptoms (Class III-V)

• IVIG: 2 g/kg over 5 days 1
• Plasmapheresis: For patients not responding to initial therapy 1
• Immediate actions for Class III-V: Permanently discontinue any causative immune checkpoint inhibitors, admit with ICU-level monitoring capability, obtain urgent neurology consultation 1

Surgical Treatment

• Thymectomy: Indicated when thymoma is identified on imaging and can lead to substantial reduction of symptoms 3
• Preoperative requirement: All patients with suspected myasthenia gravis requiring surgery must have serum anti-acetylcholine receptor antibody levels measured preoperatively to avoid respiratory failure during anesthesia 1

Novel Therapeutics

• Efgartigimod alfa and hyaluronidase-qvfc: Alternative treatment option for patients not responding to initial therapy 1
• Eculizumab: New treatment option with supporting evidence of marked improvement 5

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Critical Pitfalls and Medications to Avoid

Medications That Can Precipitate or Worsen Myasthenic Weakness

The American Academy of Neurology recommends avoiding the following medications in patients with myasthenia gravis due to potential exacerbation of symptoms: 1

• β-blockers 1
• IV magnesium 1
• Fluoroquinolones 1
• Aminoglycosides 1
• Macrolide antibiotics 1

Clinical Management Pitfalls

• Failure to recognize early respiratory involvement can be fatal—all grades of myasthenia gravis warrant thorough work-up and intervention given potential for progressive disease leading to respiratory compromise 1, 3
• Regular pulmonary function assessment is crucial in patients with generalized myasthenia gravis to monitor for respiratory compromise 1
• Dysphagia is a red-flag symptom: Present in more than 50% of cases that precede myasthenic crisis and requires urgent assessment 1
• Approximately 50% of ocular myasthenia patients show minimal response to pyridostigmine alone, which does not rule out the diagnosis and should prompt consideration of corticosteroids 1

Referral and Collaboration

• Collaboration between an experienced ophthalmologist and neurologist is necessary for diagnosis and management, particularly in patients with ocular involvement 1
• Initiation of disease-specific therapy should be deferred in primary-care settings; definitive management must be overseen by a neurologist experienced in myasthenia gravis 3

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Additional Differential Diagnoses to Consider

Conditions That May Mimic Myasthenia Gravis

• Third nerve palsy: Distinguished by pupillary abnormalities (pupils are spared in myasthenia gravis); requires immediate neuroimaging and vascular workup given risk of aneurysm or ischemia 1, 2
• Lambert-Eaton syndrome: Part of the differential for pupil-sparing ocular motility disorders 1
• Botulism: Presents with symmetric cranial nerve palsies, descending paralysis, pupillary involvement, and early gastrointestinal symptoms; consider toxin exposure history 1, 3
• Chronic progressive external ophthalmoplegia: Part of the differential for ocular myasthenia gravis 1
• Guillain-Barré syndrome: Presents with ascending weakness, sensory involvement, and elevated CSF protein by week 2 (CSF is typically normal in myasthenia gravis) 1, 3
• Brainstem lesions: Brain imaging may help exclude brainstem strokes that can mimic myasthenia gravis 1
• Orbital pathology: Orbital imaging differentiates structural lesions from myasthenia gravis 1

Features That Should Prompt Consideration of Alternative Diagnoses

• Pupillary involvement: Immediately alerts the clinician to carefully consider other etiologies, particularly third nerve palsy 1, 2
• Prominent pain: Suggests alternative diagnoses such as myositis 3
• Sensory disturbances (numbness, tingling): Absent in myasthenia gravis; evaluate for Guillain-Barré syndrome or other neuropathies 3
• Altered level of consciousness: Absent in myasthenia gravis unless sedated; should prompt search for other etiologies 3